Clinical phenotypes of adult-onset Behçet's syndrome: a comprehensive cross-sectional study in China.

Behçet's syndrome (BS) is a variant vasculitis that can involve multiple organs with inflammatory manifestations. This study aimed to provide a more comprehensive analysis of the clinical phenotypes and characteristics of BS patients. We enrolled 2792 BS patients referred from China nationwide to Huadong Hospital Affiliated to Fudan University from October 2012 to December 2022. Detailed assessments of demographic information, clinical manifestations, laboratory results, gastroscopy, and medical imaging were conducted. Cluster analysis was performed based on 13 variables to determine the clinical phenotypes, and each phenotype was characterized according to the features of BS patients. A total of 1834 BS patients were included, while 958 invalid patients were excluded. The median age at onset was 31 years (IQR, 24-40 years), and the median disease duration was 10 years (IQR, 5-15 years). Eight clusters were identified, including mucocutaneous (n = 655, 35.7%), gastrointestinal (n = 363, 19.8%), articular (n = 184, 10%), ocular (n = 223, 12.2%), cardiovascular (n = 119, 6.5%), neurological (n = 118, 6.4%), vascular (n = 114, 6.2%), and hematological phenotype (n = 58, 3.2%). Ocular (RR = 1.672 (95% CI, 1.327-2.106); P < 0.001), gastrointestinal (RR = = 1.194 (95% CI, 1.031-1.383); P = 0.018), cardiovascular (RR = = 2.582 (95% CI, 1.842-3.620); P < 0.001), and vascular (RR = = 2.288 (95% CI, 1.600-3.272); P < 0.001) involvement were more prevalent in male BS patients, while the hematological (RR = 0.528 (95% CI, 0.360-0.776); P = 0.001) involvement was more common among female patients. BS presents significant heterogeneity and gender differences. The eight phenotypes of BS patients we propose hold the potential to assist clinicians in devising more personalized treatment and follow-up strategies. Key Points • This cluster analysis divided adult-onset BS into eight clinical phenotypes. • BS demonstrates a high level of clinical heterogeneity and gender differences. • Hematologic phenotypes of BS present distinctive clinical characteristics.

PLK1-activating IFI16-STING-TBK1 pathway induces apoptosis of intestinal epithelial cells in patients with intestinal Behçet's syndrome.

Inflammatory signals from immunological cells may cause damage to intestinal epithelial cells (IECs), resulting in intestinal inflammation and tissue impairment. Interferon-γ-inducible protein 16 (IFI16) was reported to be involved in the pathogenesis of Behçet's syndrome (BS). This study aimed to investigate how inflammatory cytokines released by immunological cells and IFI16 participate in the pathogenesis of intestinal BS. RNA sequencing and real-time quantitative PCR (qPCR) showed that the positive regulation of tumor necrosis factor-α (TNF-α) production in peripheral blood mononuclear cells (PBMCs) of intestinal BS patients may be related to the upregulation of polo like kinase 1 (PLK1) in PBMCs (P = 0.012). The plasma TNF-α protein level in intestinal BS was significantly higher than in healthy controls (HCs; P = 0.009). PBMCs of intestinal BS patients and HCs were co-cultured with human normal IECs (NCM460) to explore the interaction between immunological cells and IECs. Using IFI16 knockdown, PBMC-NCM460 co-culture, TNF-α neutralizing monoclonal antibody (mAb), stimulator of interferon genes (STING) agonist 2'3'-cGAMP, and the PLK1 inhibitor SBE 13 HCL, we found that PLK1 promotes the secretion of TNF-α from PBMCs of intestinal BS patients, which causes overexpression of IFI16 and induces apoptosis of IECs via the STING-TBK1 pathway. The expressions of IFI16, TNF-α, cleaved caspase 3, phosphorylated STING (pSTING) and phosphorylated tank binding kinase 1 (pTBK1) in the intestinal ulcer tissue of BS patients were significantly higher than that of HCs (all P < 0.05). PLK1 in PBMCs of intestinal BS patients increased TNF-α secretion, inducing IEC apoptosis via activation of the IFI16-STING-TBK1 pathway. PLK1 and the IFI16-STING-TBK1 pathway may be new therapeutic targets for intestinal BS.

Clinical heterogeneity and five phenotypes identified in pediatric Behçet's syndrome: a cohort study from Shanghai Behçet's syndrome database.

OBJECTIVES: Behçet's syndrome (BS) is a rare disease of unknown etiology, with limited reports especially in pediatric BS. The clinical characteristics and phenotypes of pediatric BS as a highly heterogeneous variable vessel vasculitis were investigated in this study. METHODS: A cross-sectional study was conducted to compare clinical variables and descriptive characteristics of BS by age of onset and gender. Cluster analysis was then performed to identify the phenotypes of pediatric BS. RESULTS: A total of 2082 BS patients were included in this study, 1834 adults and 248 children. Compared with adult-onset BS, pediatric BS had a higher incidence of folliculitis [relative risks (RR) and 95% confidence interval (CI) 1.3 (1.0-1.5)], uveitis of the left eye [RR and 95% CI 2.3 (1.0-5.0)], intestinal ulcer complications [RR and 95% CI 2.1 (1.1-4.2)], pericarditis [RR and 95% CI 2.5 (1.0-6.2)], and psychiatric disorders [RR and 95% CI 2.8(1.0-7.9)], while the incidence of thrombocytopenia was lower [RR 0.2 (0.1-1.0)]. Among pediatric BS, females had more genital ulcers, while males were more likely to have skin lesions, panuveitis, vascular involvement, venous lesions, cardiac involvement, and aortic aneurysms. Cluster analysis classified pediatric BS into five clusters (C1-C5): C1 (n = 61, 24.6%) showed gastrointestinal (GI) involvement; C2 (n = 44, 17.7%) was the central nervous system (CNS) type where 23 cases overlapped joint involvement; in C3 (n = 35, 14.1%), all patients presented with arthritis or arthralgia; all patients in C4 (n = 29, 11.7%) manifested ocular involvement, with a few patients overlapping with GI involvement or joint damage; C5 (n = 79, 31.9%) was the mucocutaneous type, presenting both oral ulcers, genital ulcers, and skin lesions. CONCLUSIONS: The clinical features of pediatric and adult BS differ significantly. Male and female pediatric BS also have a distinct demography. Five phenotypes including GI, CNS, joint, ocular, and mucocutaneous types were identified for pediatric BS.

Comprehensive analysis of T-cell receptor repertoires reveals antigen-driven T-cell clusters in patients with Behçet's syndrome.

T lymphocytes are the major components of adaptive immunity in Behçet's syndrome (BS) pathology. However, the precise mechanism of T-cell-induced inflammatory condition remains to be determined. We applied bulk sequencing of the T-cell receptor (TCR) ß chain in peripheral blood samples from 45 patients with BS and 10 healthy donors as controls. TCR repertoires in BS patients displayed more clonality and less diversity than in healthy donors. Male patients exhibited lower diversity metrics of TCR and had a larger proportion in the top 10 clones than females (p = 0.016). There were no TCR clonality differences in other clinical features, such as age, disease duration, organ involvement, disease severity, and activity. By "Grouping of Lymphocyte Interactions by Paratope Hotspots" (GLIPH2) for antigen prediction, we found distinct 2477 clusters of TCR-ß sequences that potentially recognize similar antigens shared between BS patients. We observed clonal T-cell expansion in BS patients. Sexual differences in TCR clonal expansion and public TCR groups deserve further study to reveal the underline T-cell-mediated immunity in BS.

Predictors of infliximab refractory intestinal Behçet's syndrome: A retrospective cohort study from the Shanghai Behçet's syndrome database.

OBJECTIVES: This retrospective cohort study aimed to find out predictors and early biomarkers of Infliximab (IFX) refractory intestinal Behçet's syndrome (intestinal BS). METHODS: We collected the baseline clinical characteristics, laboratory parameters, and concomitant therapies of intestinal BS patients treated by IFX from the Shanghai Behçet's syndrome database. After 1 year IFX therapy, intestinal BS patients with non-mucosal healing (NMH, intestinal ulcers detected by colonoscopy) and/or no clinical remission [NCR, scores of the disease activity index for intestinal Behçet's disease (DAIBD) ≥20] were defined as IFX refractory intestinal BS. Multivariate logistic regression analysis was performed to evaluate the predictors for NMH and NCR in IFX refractory intestinal BS. RESULTS: In 85 intestinal BS patients, NMH was identified in 29 (34.12%) patients, and NCR was confirmed in 20 (23.53%) patients. Erythrocyte sedimentation rate (ESR; ≥24 mm/h) and free triiodothyronine (fT3; ≤3.3pmol/L) were the independent risk factors of NMH in IFX refractory intestinal BS. Drinking alcohol and the fT3/free thyroxine ratio (fT3/fT4; ≤0.24) were independent risk factors, and thalidomide was an independent protective factor, for NCR in intestinal BS patients treated by IFX. CONCLUSION: This study may be applicable for adjusting the therapeutic strategy and sidestepping unnecessary exposure to IFX in intestinal BS patients. Routine assessments of ESR, fT3, and fT3/fT4 ratio are helpful to identify high-risk individuals of IFX refractory intestinal BS. Thalidomide is suggested to be a concomitant therapy with IFX for intestinal BS patients.

Tofacitinib as an alternative therapy for refractory intestinal Behçet's syndrome.

Background: Intestinal Behçet's syndrome is a major cause of morbidity and mortality in Behçet's syndrome. Objectives: Current treatment challenges remain in refractory intestinal Behçet's syndrome, when patients failed first and second-line therapies. Design: We reported the efficacy and safety profiles of tofacitinib in patients with moderate-severe intestinal Behçet's syndrome in a retrospective single-center study. Methods: Treatment with glucocorticoids, immunosuppressors, or even anti-TNFα monoclonal antibodies (mAbs) had previously failed. Primary outcomes were clinical remission or low disease activity and endoscopic healing. Results: We included 13 patients; 11 were administered tofacitinib 5 mg twice daily, and 2 took tofacitinib 5 mg once daily. Nine patients achieved clinical remission after a mean treatment duration of 10.1 ± 7.0 months, and the other four had low disease activity. Follow-up endoscopy was available in 11 patients: 5 had achieved mucosal healing; the other 4 achieved marked mucosal improvement. Prednisone dosage was significantly reduced, from 30 (interquartile range: 20-30) mg/d to 2.5 (interquartile range: 0-12.5) mg/d (p < 0.001). No serious adverse event was observed. Conclusion: Tofacitinib could be an efficacious and generally well-tolerated option in patients with intestinal Behçet's syndrome refractory to conventional agents, even anti-TNFα mAbs.

Cluster analysis of phenotypes of patients with Behçet's syndrome: a large cohort study from a referral center in China.

INTRODUCTION: Behcet's syndrome (BS) is a complex, heterogeneous disorder. However, classification of its subgroups is still debated. The purpose of this study was to investigate the clinical features and aggregation of patients with BS in China, based on manifestations and organ involvements. METHODS: This was a cross-sectional study of BS patients in Huadong Hospital of Fudan University between September 2012 and January 2020. We calculated relative risks (RRs) of clinical variables according to sex. Moreover, we conducted a hierarchical cluster analysis applied according to eighteen variables to determine subgroups of patients. RESULTS: A total of 860 BS patients were included. Male sex was associated with ocular involvement (RR 2.32, 95% CI 1.67, 3.22, P < 0.0001), vascular involvement (RR 2.00, 95% CI 1.23, 3.23, P = 0.004), cardiac lesion (RR 5.46, 95% CI 2.33, 12.77, P < 0.0001), and central nervous system involvement (RR 2.95, 95% CI 1.07, 6.78, P = 0.007) and was negatively associated with genital ulcers (RR 0.84, 95% CI 0.79, 0.91, P < 0.0001). Five clusters (C1-C5) were observed. C1 (n = 307) showed the skin and mucosa type. In C2 (n = 124), all had articular involvement, barely having major organ involvement except for 18 cases with intestinal lesions. In C3 (n = 156), the gastrointestinal type, 144 patients presented with intestinal involvement, and 36 patients with esophageal ulcers. In C4 (n = 142), all subjects presented with uveitis. C5 (n = 131) consisted of 44 patients with cardiac lesions, 58 with vascular involvement, and 26 cases having central nervous system involvement. CONCLUSION: Our analysis confirmed sex differences in phenotypes of BS. Cluster analysis identified gastrointestinal, uveitis, and cardiovascular involvement cluster separately in different subsets, which represents the most commonly involved organs. Further research is required to replicate and clarify the patterns of phenotype in BS.

Demography of vascular Behcet's disease with different gender and age: an investigation with 166 Chinese patients.

BACKGROUND: The Clinical features of vascular Behcet's disease (BD) are not well understood because there are few studies. Our study aimed to investigate characteristics of vascular BD in both genders in different age groups. RESULTS: We enrolled 923 patients with BD who presented to our hospital with adequate medical histories and proper vascular screening exams. The raw incidence rate of vascular BD was 17.98% (166/923). The ratio of vascular BD in male to female patients was 1.868 (p = 0.0004, 95% confidence interval (CI): 1.317 to 2.625). There was a tendency towards higher ESR and CRP in vascular BD patients than in mucocutaneous, but the difference was not significant. The most susceptible affected vessels were cerebral (29.6% in males, 59.4% in females) and lower limb vessels (31.2% in males, and 17.2% in females). The incidence of vascular involvement in younger (< 50 years old) and older (≥ 50 years old) patients were similar, with ratios of 16.58% (122/736) and 23.53% (44/187) respectively. However, in females, younger patients were less likely to have vascular involvement than were older patients (11.43% vs. 20% p = 0.0328, OR: 0.5161, 95% CI: 0.2874 to 0.912). Aneurysm or pseudoaneurysm was diagnosed in 1.84% (17/923) patients, mostly in male patients (p < 0.05, OR: 3.221, 95% CI: 1.097 to 9.112). Twenty vascular BD patients were followed up, and the age at BD diagnosis was 33.23 ± 11.56 year. This did not differ statistically with their age at vascular involvement (36.15 ± 9.52 years). Ages of vascular BD patients did not differ significantly from those of mucocutaneous BD patients (n = 143) in both males and females. CONCLUSION: Vascular BD, including lethal types of aneurysm is more likely to occur in male patients. The female patients has a similar incidence rate with the males in their postmenopausal age. There was no evidence of progression course from mucocutaneous BD to vascular involvement.

Incidence and risk factors for anemia among newly-diagnosed intestinal Behcet's disease patients.

BACKGROUND: To investigate the incidence, characteristics, and potential risk factors of anemia in patients with newly-diagnosed intestinal Behcet's disease (BD). METHODS: In this cross-sectional study, 106 newly-diagnosed intestinal BD patients were identified, and a gender-, age- and organ involvement-matched control group of 241 non-intestinal BD patients was established. Hemoglobin (Hb) levels below 120 g/L in women and 130 g/L in men were diagnosed as anemia; these were further classified as mild (Hb ≥ 90 g/L), moderate (60  g/L ≤ Hb < 90  g/L), and severe (Hb < 60 g/L) anemia for both genders. The prevalence, type and severity of anemia in these patients were assessed. Logistic regression was performed to analyze the relationship between clinical variables and anemia in newly-diagnosed intestinal BD patients. RESULTS: The prevalence of anemia was 60.38% in newly-diagnosed patients with intestinal BD, significantly higher than those with non-intestinal BD (27.80%). Patients with intestinal BD had lower Hb, higher levels of C-reactive protein (CRP) and higher erythrocyte sedimentation rates (ESR) than did patients with non-intestinal BD (P < 0.05). The majority of patients had mild-to-moderate anemia. The most common type of anemia found in both groups was normocytic normochromic anemia (56.25% for intestinal BD and 59.70% for non-intestinal BD). Multivariate logistic regression showed that the independent risk factors for anemia were disease activity index (DAIBD) (OR = 4.949, 95% CI: 1.504-16.282), higher levels of ESR (OR = 1.058, 95% CI: 1.019-1.099), and lower body mass index (BMI) (OR = 0.843, 95% CI: 0.727-0.977) for newly-diagnosed intestinal BD patients. CONCLUSION: Anemia is common in patients with newly-diagnosed intestinal BD. Although typically mild or moderate, anemia may closely relate with disease activity.

High Incidence of Gastrointestinal Ulceration and Cytogenetic Aberration of Trisomy 8 as Typical Features of Behçet's Disease Associated with Myelodysplastic Syndrome: A Series of 16 Consecutive Chinese Patients from the Shanghai Behçet's Disease Database and Comparison with the Literature.

This study aimed to investigate the characteristics of Chinese patients with Behçet disease (BD) and myelodysplastic syndrome (MDS) and explore the role played by trisomy 8. This was a retrospective study of patients with BD and MDS from the Shanghai Behçet's disease database who were diagnosed between October 2012 and July 2017. There were 805 patients with BD and 16 also had MDS. Trisomy 8 was examined in patients with BD-MDS and some patients with gastrointestinal (GI) BD. Patients with BD and MDS (16/805; 2%) were more likely to be female and older; display fever and intestinal lesions; have lower leukocyte count, hemoglobin, platelet count; and show higher C-reactive protein and erythrocyte sedimentation rate (ESR) than patients with BD without MDS (all P < 0.05). Trisomy 8 was common (81.3%) in patients with BD-MDS. Ulcers in the ileocecal region were more frequently seen in intestinal patients with BD-MDS than in BD without MDS (90.0% versus 48.9%; P = 0.032). GI ulceration is common in patients with BD-MDS. Cytogenetic aberrations, especially trisomy 8, may play a role in the pathogenesis of intestinal involvement in patients with BD-MDS.

Effectiveness and safety of Glycyrrhizae Decoction for Purging Stomach-Fire in Behcet disease patients: Study protocol for a randomized controlled and double-blinding trail.

BACKGROUND: Behcet disease (BD) is a worldwide-occurred autoimmune disorder and currently lack of optional successful treatment. An ancient traditional Chinese medical formula called Glycyrrhizae Decoction for Purging Stomach-Fire (GDPSF) was recorded and nowadays has been observed to be effective for BD patients. However, the strict randomized controlled and double-blinding trail is needed to further assess this alternative medicine. METHODS: To ascertain the potential effects and safety of GDPSF for BD patients and to determine whether combination application of GDPSF and thalidomide could possibly reduce the side effects and increase effectiveness for BD management, we will conduct a randomized, double blind, controlled clinical trial. Patients enrolled will be randomly assigned into 3 groups: GDPSF group, thalidomide group, and integrative group (treated by both GDPSF and thalidomide). Participants will receive treatment for 6 months and accept a 12 months follow-up. Before and after treatment, clinical manifestations, blood tests, thalidomide dosage, remission levels, quality of life, and satisfactory levels will be assessed. The data of assessments on each group before and after treatments will be collected and analyzed through historical control, while between groups through intergroup control. Then statistical analysis will be applied to assess the effects and safety. DISCUSSION: This study protocol will assess the effects and safety of GDPSF for BD patients GDPSF. Combination application of GDPSF and thalidomide might be a new integrative medical method for BD patients. TRIAL REGISTRATION: Chinese Clinical Registry (ChiCTR-ONC-16009621) on Oct. 2016 http://www.chictr.org.cn/showproj.aspx?proj=16395.

Long-Term Outcomes and Predictors of Sustained Response in Patients with Intestinal Behcet's Disease Treated with Infliximab.

BACKGROUND: Intestinal Behcet's disease (BD) is a specific subtype of BD. Effective drug therapy for intestinal BD remains elusive. AIMS: To investigate long-term outcomes and identify predictors of sustained response in intestinal BD patients receiving infliximab (IFX) treatment. METHODS: The medical records were reviewed of patients received IFX from September 2012 to March 2016. The cumulative probabilities of sustained response were calculated using the Kaplan-Meier. Predictor factors for sustained response were accessed by receiver operating characteristic curve. RESULTS: Totally, 27 active intestinal BD patients were enrolled. Sustained responses were observed in 17 patients, after a median follow-up duration 24 months (interquartile range 9-37). The proportion of clinical remission at week 14, 30, and 52 had occurred in 84.6, 70, and 70%, respectively, with the proportion of clinical remission of 69.2, 40, and 55%. The mucosal healing (MH) rate at week 14 was 72%. Kaplan-Meier estimated patients with achievement of clinical and biological responses at week 14 or MH was likely to remain sustained clinical response. ROC curve analysis revealed CRP level (of 6.85 mg/L) at week 14 is a potential predictor for discriminating patients with sustained response from relapse, with an area under the curve values of 0.837. CONCLUSIONS: IFX is effective and safe for induction and maintenance therapy in Chinese patients with moderate-to-severe active intestinal BD. Early achievement of clinical response and mucosal healing might associate long-term response. A lower CRP level seems to be associated with a more benign clinical course.

Infliximab associated with life-threatening lung infection in a patient with Behcet disease with intestinal and hematopoietic system involvement: A case report.

RATIONALE: Tumor necrosis factor (TNF-α) participates in the pathophysiology of Behcet's disease (BD) and myelodysplastic syndrome (MDS). Infliximab is recommaned for the most severe type of BD, however, there is little evidence for its effectiveness in BD associated MDS. PATIENT CONCERNS: A 46-year-old female, initially diagnosed with intestinal BD and leukopenia was later diagnosed as MDS. Treatement with infliximab and other immunoregulators lead to life-threatening pneumonia. DIAGNOSIS: Intestinal BD associated with MDS involving trisomy 8. INTERVENTIONS: The patient initially treated with methylprednisolone, thalidomide, cyclosporine A, and infliximab, which lead to severe lung infection. Therefore, the patient was transferred to Intensive Care Unit for life supportive, anti-infection and immune improving therapy. OUTCOMES: The patient survived from the lung infection. With combination of methylprednisolone, thalidomide and cyclosporine A, the patient recovered from her intestinal ulceration and MDS manifestations. LESSONS: Infliximab treatment may not benefit a patient with BD associated with MDS but place the patient at risk of infection.